title: Cordycepin regulates GSK-3β/β-catenin signaling in human leukemia cells.
abstract: BACKGROUND
  Leukemia stem cells (LSCs) are a limitless cell source for the initiation and maintenance of leukemia. Activation of the Wnt/β-catenin pathway is required for the survival and development of LSCs. Therefore, targeting β-catenin is considered a therapeutic strategy for the treatment of leukemia. The goal of this study was to explore whether cordycepin, an active component of the traditional medicine Cordyceps sinensis, regulates β-catenin expression in leukemia cells.
  
  
  RESULTS
  In this study, we found that cordycepin significantly suppressed cell proliferation in all malignant cancer cells, including U937, K562, A549, HepG2, SK-Hep1 and MCF7 in a dose-dependent manner. However, cordycepin reduced β-catenin levels in U937, K562 and THP1 leukemia cells and had no effect on other solid cancer cells. In addition, treatment with cordycepin significantly suppressed leukemia colony formation in soft agar assay. Cordycepin enhanced proteasome-dependent degradation and inhibited nuclear translocation of β-catenin in leukemia cells. Cordycepin-reduced β-catenin stability was restored by the addition of a pharmacological inhibitor of GSK-3β, indicating that cordycepin-suppressed β-catenin stability is mediated by the activation of GSK-3β. Furthermore, cordycepin abolished the effect of Wnt3a-induced β-catenin in leukemia cells. In addition, cordycepin-impaired β-catenin is regulated by Akt activation but is not significantly influenced by AMPK or mTOR signal pathways.
  
  
  CONCLUSIONS
  Our findings show for the first time that codycepin selectively reduces β-catenin stability in leukemia but not in other solid tumor cells. This suppressive effect is mediated by regulating GSK-3β. A synergistic combination of cordycepin with other treatments should be used as a novel strategy to eradicate leukemia via elimination of LSCs.
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan ; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Bor-Sheng
authors.initials: BS
authors.lastname: Ko
authors.forename: Yi-Jhu
authors.initials: YJ
authors.lastname: Lu
authors.forename: Wen-Ling
authors.initials: WL
authors.lastname: Yao
authors.forename: Tzu-An
authors.initials: TA
authors.lastname: Liu
authors.forename: Shean-Shong
authors.initials: SS
authors.lastname: Tzean
authors.forename: Tang-Long
authors.initials: TL
authors.lastname: Shen
authors.forename: Jun-Yang
authors.initials: JY
authors.lastname: Liou
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003839:Deoxyadenosines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005455:Fluorescent Antibody Technique; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014410:Tumor Stem Cell Assay; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D003839:Deoxyadenosines; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C058120:cordycepin